PARTICULATE-BASED IN VIVO MODULATION FOR IMMUNOTHERAPY OF RHEUMATOID ARTHRITIS PROJECT SUMMARY/ ABSTRACT Rheumatoid arthritis (RA) is a chronic, systemic, auto-inflammatory disease that affects approximately 1% of adults worldwide, and commonly results in joint destruction and significant impairment in the quality of life. The underlying cause of RA is dendritic cell (DC) activation of antigen-specific T cell subsets in the joints, which drive inflammatory responses to the synovial membrane that are typically characterized by hyperplasia, increased vascularity, inflammatory cell infiltration and over production of pro-inflammatory cytokines (particularly IL-1, IL-6 and TNF-?) by monocytes, macrophages and synovial fibroblasts. Due to their critical role in RA progression, these cytokines have become the major therapeutic targets for RA therapy. Other therapeutic approaches include administration of steroids, as well as, anti-angiogenesis drugs. However, these strategies do not address the root cause of RA ? stimulation of T lymphocytes by DCs. A number of factors are known to promote advantageous dendritic cell responses in experimental systems for autoimmune diseases. However, systemic delivery of these agents often results in significant harmful off-target effects. The Lewis Lab at UC, Davis is developing a novel, biomaterial-based, microparticle `anti-vaccine' for in vivo co-delivery of pro-tolerance factors and autoantigens, targeted to DCs. Exogenous conditioning of DCs with certain immuno-modulatory agents has been shown to induce a pro-tolerance DC phenotype, as well as, ameliorate RA. However, vaccination with a microparticle anti-vaccine promises to correct aberrant autoimmune responses, whilst circumventing problems associated with DC-based cellular therapy such as DC phenotypic stability and survivability, and autoantigen plurality. The long-term goal is to develop a modular, anti-vaccine system for autoimmune disease therapy. The overall objective of this R01 proposal is to engineer a multi-component, MP anti-vaccine to attenuate RA progression in an aggressive, murine RA model, and investigate the extent of immune modulation following anti-vaccination. The central hypothesis is that this MP anti-vaccine will induce autoantigen-specific tolerance by targeted delivery of model-relevant autoantigen and tolerance-inducing factors to immune cells, especially DCs, thereby generating aAg-specific tDCs that will retrain downstream adaptive responses and promote the remission of RA. This hypothesis will be tested by pursuing four specific aims: 1) Assess the effect of material properties and anti-vaccine agent presentation on the tolerogenicity of DC immunotherapy; 2) Evaluate the capacity of this platform system to limit RA in the FIA-CIA mouse model; 3) Investigate mechanisms of immune tolerance using well-defined antigen-specific mouse models; and 4) Investigate preliminary manufacturing and safety metrics with an eye towards clinical translation. The approach is innovative, in the applicant's opinion, because it departs from the status quo by generating specific tolerance- inducing cellular mediators in vivo with a simple subcutaneous injection of polymeric microparticles. Ultimately, the research and development of this system has the potential to significantly stem the growing epidemic of autoimmunity in the US.